Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy.

Targeted delivery of therapeutic drugs to fibrosis-promoting macrophages (FPMs) holds promise as a challenging yet effective approach for the treatment of idiopathic pulmonary fibrosis (IPF). Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues. FPM targeting was achieved by functionalizing the nanocarrier surface with an M2-like FPM binding peptide (M2pep). As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80 % of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur). Importantly, the released Mn2+ and curcumin after the degradation of M2NP-BLZ@Mn-Cur accumulated in the fibrotic lung tissue, which can alleviate inflammation and oxidative stress reactions, thereby further improving IPF therapy. This study presents a novel strategy with promising prospects for molecular-targeted fibrosis therapy. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs)- based nanocarriers equipped with both fibrosis-promoting macrophage (FPM)-specific targeting ability and therapeutic drugs are appealing for pulmonary fibrosis treatment. Here, we prepared M2pep (an M2-like FPM binding peptide)-modified and BLZ945 (a small molecule inhibitor of CSF1/CSF-1R axis)-loaded Mn-curcumin MOF nanoparticles (M2NP-BLZ@Mn-Cur) for pulmonary fibrosis therapy. The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mn2+and curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles.

Vincamine as an agonist of G protein-coupled receptor 40 effectively ameliorates pulmonary fibrosis in mice.

BACKGROUND: Pulmonary fibrosis (PF) is an irreversible and fatal lung disease with limited therapeutic options. G protein-coupled receptor 40 (GPR40) has been developed as a promising therapeutic target for metabolic disorders and functions potently in varied pathological and physiological processes. Vincamine (Vin) is a monoterpenoid indole alkaloid originated from Madagascar periwinkle and was reported as a GPR40 agonist in our previous work. PURPOSE: Here, we aimed to clarify the role of GPR40 in PF pathogenesis by using the determined GPR40 agonist Vin as a probe and explore the potential of Vin in ameliorating PF in mice. METHODS: Pulmonary GPR40 expression alterations were assessed in both PF patients and bleomycin-induced PF mice (PF mice). Vin was used to evaluate the therapeutic potential of GPR40 activation for PF and the underlying mechanism was intensively investigated by assays against GPR40 knockout (Ffar1-/-) mice and the cells transfected with si-GPR40 in vitro. RESULTS: Pulmonary GPR40 expression level was highly downregulated in PF patients and PF mice. Pulmonary GPR40 deletion (Ffar1-/-) exacerbated pulmonary fibrosis as evidenced by the increases in mortality, dysfunctional lung index, activated myofibroblasts and extracellular matrix (ECM) deposition in PF mice. Vin-mediated pulmonary GPR40 activation ameliorated PF-like pathology in mice. Mechanistically, Vin suppressed ECM deposition by GPR40/ß-arrestin2/SMAD3 pathway, repressed inflammatory response by GPR40/NF-κB/NLRP3 pathway and inhibited angiogenesis by decreasing GPR40-mediated vascular endothelial growth factor (VEGF) expression in the region of interface to normal parenchyma in pulmonary fibrotic tissues of mice. CONCLUSION: Pulmonary GPR40 activation shows promise as a therapeutic strategy for PF and Vin exhibits high potential in treating this disease.